VCV001722510.4 - ClinVar

NM_002224.4(ITPR3):c.4271C>T (p.Thr1424Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002224.4(ITPR3):c.4271C>T (p.Thr1424Met)

Variation ID: 1722510 Accession: VCV001722510.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.31 6: 33680375 (GRCh38) [ NCBI UCSC ] 6: 33648152 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 13, 2022	Sep 29, 2024	Oct 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002224.4:c.4271C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002215.2:p.Thr1424Met	missense
NM_002224.3:c.4271C>T
NC_000006.12:g.33680375C>T
NC_000006.11:g.33648152C>T
NG_027729.2:g.64055C>T

... more HGVS ... less HGVS

Protein change

T1424M

Other names

Canonical SPDI

NC_000006.12:33680374:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 147267.0001 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ITPR3		-	-	GRCh38 GRCh37	404	421

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Charcot-Marie-Tooth disease, demyelinating, type 1J	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 26, 2023	RCV002305679.4
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 4, 2023	RCV004719253.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Sep 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease, demyelinating, type 1J Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004042755.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: ACMG criteria used to clasify this variant: PS3_MOD, PP3_MOD, PS4_SUP, PM2_SUP
Likely pathogenic (Oct 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease, demyelinating, type 1J Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004238252.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely pathogenic (May 04, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005324987.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Segregates with inherited peripheral neuropathy in a mother and two daughters reported in the published literature (Schabhuttl et al., 2014); Functional studies indicate that T1424M … (more) Segregates with inherited peripheral neuropathy in a mother and two daughters reported in the published literature (Schabhuttl et al., 2014); Functional studies indicate that T1424M generates a leaky but functional channel (Terry et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32949214, 24627108, 36444295) (less)
Pathogenic (May 01, 2014)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1J Affected status: not provided Allele origin: germline	OMIM Accession: SCV002599089.1 First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022	Publications: PubMed (1) PubMed: 24627108 Comment on evidence: In a woman and her 2 daughters (family HMSN-D6) with autosomal dominant demyelinating Charcot-Marie-Tooth disease type 1J (CMT1J; 620111), Schabhuttl et al. (2014) identified a … (more) In a woman and her 2 daughters (family HMSN-D6) with autosomal dominant demyelinating Charcot-Marie-Tooth disease type 1J (CMT1J; 620111), Schabhuttl et al. (2014) identified a heterozygous c.4271C-T transition in the ITPR3 gene, resulting in a thr1424-to-met (T1424M) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Linkage analysis was consistent with the findings. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that ITPR3 is expressed in Schwann cells and controls Ca(2+) signaling at the gap junction in peripheral nerves. Exome sequencing also identified a heterozygous missense variant (V234I) in the TEC gene (600583) that segregated with the disorder, but was not considered to be a candidate for the phenotype. Clinical details were limited, but the proband (one of the daughters) was noted to have onset of peripheral neuropathy affecting the lower limbs at 40 years of age. She had mild sensory impairment and areflexia of the lower limbs. Motor nerve conduction studies detected a value of 34.7 m/s. (less)

Comment:

Segregates with inherited peripheral neuropathy in a mother and two daughters reported in the published literature (Schabhuttl et al., 2014); Functional studies indicate that T1424M generates a leaky but functional channel (Terry et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32949214, 24627108, 36444295)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges.	Schabhüttl M	Journal of neurology	2014	PMID: 24627108

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_002224.4(ITPR3):c.4271C>T (p.Thr1424Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...